molecules
Review
On the Use of Iron in Organic Chemistry
Arnar Guðmundsson1and Jan-E. Bäckvall1,2,*
1 Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden; arnar.gudmundsson@su.se
2 Department of Natural Sciences, Mid Sweden University, Holmgatan 10, 85179 Sundsvall, Sweden
* Correspondence: jeb@organ.su.se; Tel.:+46-08-674-71-78
Received: 2 March 2020; Accepted: 10 March 2020; Published: 16 March 2020 Abstract: Transition metal catalysis in modern organic synthesis has largely focused on noble transition metals like palladium, platinum and ruthenium. The toxicity and low abundance of these metals, however, has led to a rising focus on the development of the more sustainable base metals like iron, copper and nickel for use in catalysis. Iron is a particularly good candidate for this purpose due to its abundance, wide redox potential range, and the ease with which its properties can be tuned through the exploitation of its multiple oxidation states, electron spin states and redox potential.
This is a fact made clear by all life on Earth, where iron is used as a cornerstone in the chemistry of living processes. In this mini review, we report on the general advancements in the field of iron catalysis in organic chemistry covering addition reactions, C-H activation, cross-coupling reactions, cycloadditions, isomerization and redox reactions.
Keywords: iron; organic synthesis; C-H activation; C-C coupling
1. Introduction
Iron is the most abundant element on Earth by mass and is used ubiquitously by living organisms [1].
The ability of iron to assume many oxidation states (from −2 up to+6) coupled with its low toxicity makes it an attractive, versatile and useful catalyst in organic synthesis. The wide range of oxidation states available for iron and its ability to promote single electron transfer (SET) allows it to cover a wide range of transformations. In low oxidation states, iron becomes nucleophilic in character and takes part in reactions such as nucleophilic substitutions, reductions and cycloisomerizations. At higher oxidation states, iron behaves as a Lewis acid, activating unsaturated bonds and at very high oxidation states (+3 to +5) iron complexes can take part in C-H activation. Due to iron’s central position in the periodic table, it can have the property of both an “early” and “late” transition metal and with the many oxidation states available, any type of reaction is, in principle, within reach. Iron cations also bind strongly to many N- and O-based ligands, and these ligands can replace phosphine ligands in iron chemistry.
As the atmosphere on Earth changed following the Great Oxidation Event about 2.4 billion years ago, ferrous (+2) iron complexes became less stable and ferric (+3) complexes became predominant [2].
Iron in its ferric oxidation state typically forms complexes that are water-insoluble like hematite (Fe2O3) or magnetite (Fe3O4), especially under basic conditions when exposed to air. This propensity of iron complexes to precipitate can be a hindrance for catalysis, although, despite the fact that ferric complexes are mostly water-insoluble at biological pH, iron is still the most common transition metal in living organisms and is indispensable for the chemical processes of life—oxygen binding, electron transport, DNA synthesis, and cell proliferation, to name only a few.
Modern catalysis has been dominated by noble transition metals, such as palladium, platinum, ruthenium and iridium, and these metals have been used in a wide range of reactions. The main
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advantage that noble transition metals have over their base counterparts is their preference for undergoing two-electron processes. They do, however, have significant drawbacks: high cost, non-renewable supply and/or precarious toxicological and ecological properties. These factors may not pose too much of a problem for academic research, but have profound implications for industry and for the future of sustainable chemistry. It is for these reasons that attention has shifted towards base transition metals like iron, copper and nickel. Iron is particularly well suited as it is the second most abundant metal in the Earth’s crust after aluminum and is consequently attractive economically and ecologically. Despite these advantages of iron, organoiron catalysts tend to suffer from serious drawbacks such as difficult synthetic pathways, lack of robustness, poor atom economy and low activity or enantioselectivity. Although circumventing these limitations will be necessary for iron catalysis to reach its full potential, base metal catalysis will no doubt gain importance in the future and it is reasonable to think that base metals such as iron will eventually supplant the traditional dominance of noble transition metals as the field matures. In recent times, the area of iron catalysis has exploded and Beller in 2008 and Bolm in 2009 declared that the age of iron has begun [3,4]. An intriguing outlook on the future of homogeneous iron catalysis was published in 2016 by Fürstner [5].
This review focuses on the recent advancements in iron catalysis pertaining to organic chemistry from 2016 to February 2020. An excellent and comprehensive review from 2015 by Knölker on all the types of iron-catalyzed reactions discussed in this review in addition to others can be consulted for the interested reader [6]. Other more specialized reviews may be found in each respective subsection.
It should be mentioned that metathesis reactions are omitted from this review.
2. Iron in Organic Synthesis
Organoiron chemistry began in 1891 with the discovery of iron pentacarbonyl by Mond and Berthelot [7,8]. It was used sixty years later industrially in the Reppe process of hydroformylation of ethylene to form propionaldehyde and 1-propanol in basic solutions [9]. An important event was the discovery of ferrocene in 1951 [10], the structure of which was determined in 1952 [11,12] and led to the Nobel prize being awarded to Wilkinson and Fischer in 1973. The discovery of the Haber–Bosch process was an additional milestone in iron chemistry. The latter process uses an inorganic iron catalyst for the production of ammonia and sparked an agricultural revolution [13,14]. In modern organoiron chemistry, iron is used in a great number of diverse reactions, as will be apparent from this review, though perhaps, just as in the chemistry of life, its most ubiquitous role is in redox chemistry.
2.1. Addition Reactions
The first example of an iron-catalyzed racemization of alcohols was reported in 2016 with the use of an iron pincer catalyst [15]. Between 2016 and 2017, the groups of Bäckvall [16] and Rueping [17]
independently reported the dynamic kinetic resolution (DKR) of sec-alcohols using a combination of iron catalysis for racemization and a lipase for resolution, which demonstrates a useful combination of enzyme and transition metal catalysis (Scheme1). In one study, Knölkers complex (II) was used directly [17], and in the other study, a bench-stable precursor to Knölkers complex (II), iron tricarbonyl complex I, was used, which was activated through oxidative decarbonylation with TMANO to form coordinatively unsaturated iron complex I’ [16]. In the latter study, various benzylic and aliphatic esters could be produced in good to excellent yields with excellent ee. Two different enzymes, Candida antarctica lipase B (CalB/Novozyme 435) and Burkholderia cepasia (PS-C), could be used and the procedure could be reproduced on gram-scale. The group of Zhou also reported a related work using hexanoate as the acyl donor [18]. Rodriguez published a review on the synthesis, properties and reactivity of this interesting class of iron catalysts in 2015 [19].
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90
Scheme 1. Bäckvall’s and Rueping’s DKR of sec-alcohols.
91
The indole ring is a ubiquitous heterocyclic motif in natural products and methods for
92
constructing chiral polycyclic systems with indole skeletons has attracted considerable attention. In
93
2017, the group of Zhou reported the first intramolecular enantioselective cyclopropanation of
94
indoles that was catalyzed either by iron or copper in the presence of a chiral ligand (Scheme 2) [20].
95
Many functional groups were tolerated and various cyclopropanated indoles were prepared in high
96
to excellent yields and in almost all cases with excellent ee. The mechanism of the enhancement of
97
the enantioselectivity is currently unknown, although the R2 group was found to be important and
98
had to be different from hydrogen for the reaction to proceed.
99
100
Scheme 2. Zhou’s enantioselective cyclopropanation.
101
Hydroamination of alkenes is an atom-economic approach and the amines produced are some
102
of the most common functionalities found in fine chemicals and pharmaceuticals. Hydroamination
103
of terminal alkenes typically gives the Markovnikov product selectivity, but in 2019 the group of
104
Wang reported the first iron-catalyzed anti-Markovnikov addition of allylic alcohols [21]. For this
105
purpose, an iron-PNP pincer complex was used. The reaction proceeds through a
106
hydrogen-borrowing strategy where the iron complex temporarily activates the alcohol by
107
dehydrogenation to the α,β-unsaturated carbonyl compound. The latter compound reacts with an
108
amine to form an iminium ion, which undergoes conjugate additon at the β-position with another
109
amine followed by hydrolysis and reduction to give the product. Various amines were produced in
110
good yields with this method. Interestingly, hydroamidation could also be performed.
111
Scheme 1.Bäckvall’s and Rueping’s DKR of sec-alcohols.
The indole ring is a ubiquitous heterocyclic motif in natural products and methods for constructing chiral polycyclic systems with indole skeletons has attracted considerable attention. In 2017, the group of Zhou reported the first intramolecular enantioselective cyclopropanation of indoles that was catalyzed either by iron or copper in the presence of a chiral ligand (Scheme2) [20]. Many functional groups were tolerated and various cyclopropanated indoles were prepared in high to excellent yields and in almost all cases with excellent ee. The mechanism of the enhancement of the enantioselectivity is currently unknown, although the R2group was found to be important and had to be different from hydrogen for the reaction to proceed.
90
Scheme 1. Bäckvall’s and Rueping’s DKR of sec-alcohols.
91
The indole ring is a ubiquitous heterocyclic motif in natural products and methods for
92
constructing chiral polycyclic systems with indole skeletons has attracted considerable attention. In
93
2017, the group of Zhou reported the first intramolecular enantioselective cyclopropanation of
94
indoles that was catalyzed either by iron or copper in the presence of a chiral ligand (Scheme 2) [20].
95
Many functional groups were tolerated and various cyclopropanated indoles were prepared in high
96
to excellent yields and in almost all cases with excellent ee. The mechanism of the enhancement of
97
the enantioselectivity is currently unknown, although the R2 group was found to be important and
98
had to be different from hydrogen for the reaction to proceed.
99
100
Scheme 2. Zhou’s enantioselective cyclopropanation.
101
Hydroamination of alkenes is an atom-economic approach and the amines produced are some
102
of the most common functionalities found in fine chemicals and pharmaceuticals. Hydroamination
103
of terminal alkenes typically gives the Markovnikov product selectivity, but in 2019 the group of
104
Wang reported the first iron-catalyzed anti-Markovnikov addition of allylic alcohols [21]. For this
105
purpose, an iron-PNP pincer complex was used. The reaction proceeds through a
106
hydrogen-borrowing strategy where the iron complex temporarily activates the alcohol by
107
dehydrogenation to the α,β-unsaturated carbonyl compound. The latter compound reacts with an
108
amine to form an iminium ion, which undergoes conjugate additon at the β-position with another
109
amine followed by hydrolysis and reduction to give the product. Various amines were produced in
110
good yields with this method. Interestingly, hydroamidation could also be performed.
111
Scheme 2.Zhou’s enantioselective cyclopropanation.
Hydroamination of alkenes is an atom-economic approach and the amines produced are some of the most common functionalities found in fine chemicals and pharmaceuticals. Hydroamination of terminal alkenes typically gives the Markovnikov product selectivity, but in 2019 the group of Wang reported the first iron-catalyzed anti-Markovnikov addition of allylic alcohols [21]. For this purpose, an iron-PNP pincer complex was used. The reaction proceeds through a hydrogen-borrowing strategy where the iron complex temporarily activates the alcohol by dehydrogenation to the α,β-unsaturated carbonyl compound. The latter compound reacts with an amine to form an iminium ion, which undergoes conjugate additon at the β-position with another amine followed by hydrolysis and reduction to give the product. Various amines were produced in good yields with this method.
Interestingly, hydroamidation could also be performed (Scheme3).
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112
Scheme 3. Wang’s iron-catalyzed anti-Markovnikov hydroamination.
113
C-C and C-N bonds are important bonds in organic chemistry and one of the most effective
114
ways of creating these bonds simultaneously is through the carboamination of olefins. In 2017, the
115
group of Bao reported the diastereoselective construction of amines and disubstituted β-amino acids
116
through the carboamination of olefins (Scheme 4) [22]. Aliphatic acids were used as an alkyl source
117
and nitriles as a nitrogen source. The protocol could be performed on a gram-scale and various
118
carboamination products were obtained in good yields and excellent diastereoselectivity. The choice
119
of acid was found to have a strong effect on the diastereoselectivity. TsOH was used for the
120
carboamination of olefins, but for the carboamination of esters, binary and ternary acids had a more
121
positive effect over monoacids, with H2SO4 giving the best result. The addition of the nitrile group
122
was found, through Density Functional Theory (DFT) calculations, to be
123
diastereoselectivity-determining, and hyperconjugation was proposed to account for the
124
anti-selectivity.
125
126
Scheme 4. Bao’s carboamination.
127
Organosilicon compounds have significant chemical, physical and bioactive properties and an
128
example of these compounds is 1-amino-2-silylalkanes, which have, in recent times, emerged as
129
candidates for pharmaceutical development. Silicon-containing compounds are generally made
130
through hydrosylilation or dehydrogenative silylation, but in 2017 the group of Luo reported the
131
first iron-catalyzed synthesis of 1-amino-2-silylalkanes through the 1,2-difunctionalization of
132
styrenes and conjugated alkenes (Scheme 5) [23]. Di-tert-butyl-peroxide (DTBP) was used as an
133
oxidant in the reaction. Amines, amides and carbon nucleophiles could be employed and delivered
134
the corresponding products in mostly good yields. The reaction was proposed to proceed via a
135
silicon-centered radical from oxidative cleavage of the Si-H bond followed by addition across the
136
C=C bond and a N-H oxidative functionalization cascade.
137
138
Scheme 3.Wang’s iron-catalyzed anti-Markovnikov hydroamination.
C-C and C-N bonds are important bonds in organic chemistry and one of the most effective ways of creating these bonds simultaneously is through the carboamination of olefins. In 2017, the group of Bao reported the diastereoselective construction of amines and disubstituted β-amino acids through the carboamination of olefins (Scheme4) [22]. Aliphatic acids were used as an alkyl source and nitriles as a nitrogen source. The protocol could be performed on a gram-scale and various carboamination products were obtained in good yields and excellent diastereoselectivity. The choice of acid was found to have a strong effect on the diastereoselectivity. TsOH was used for the carboamination of olefins, but for the carboamination of esters, binary and ternary acids had a more positive effect over monoacids, with H2SO4giving the best result. The addition of the nitrile group was found, through Density Functional Theory (DFT) calculations, to be diastereoselectivity-determining, and hyperconjugation was proposed to account for the anti-selectivity.
Molecules 2020, 25, x FOR PEER REVIEW 4 of 20
112
Scheme 3. Wang’s iron-catalyzed anti-Markovnikov hydroamination.
113
C-C and C-N bonds are important bonds in organic chemistry and one of the most effective
114
ways of creating these bonds simultaneously is through the carboamination of olefins. In 2017, the
115
group of Bao reported the diastereoselective construction of amines and disubstituted β-amino acids
116
through the carboamination of olefins (Scheme 4) [22]. Aliphatic acids were used as an alkyl source
117
and nitriles as a nitrogen source. The protocol could be performed on a gram-scale and various
118
carboamination products were obtained in good yields and excellent diastereoselectivity. The choice
119
of acid was found to have a strong effect on the diastereoselectivity. TsOH was used for the
120
carboamination of olefins, but for the carboamination of esters, binary and ternary acids had a more
121
positive effect over monoacids, with H2SO4 giving the best result. The addition of the nitrile group
122
was found, through Density Functional Theory (DFT) calculations, to be
123
diastereoselectivity-determining, and hyperconjugation was proposed to account for the
124
anti-selectivity.
125
126
Scheme 4. Bao’s carboamination.
127
Organosilicon compounds have significant chemical, physical and bioactive properties and an
128
example of these compounds is 1-amino-2-silylalkanes, which have, in recent times, emerged as
129
candidates for pharmaceutical development. Silicon-containing compounds are generally made
130
through hydrosylilation or dehydrogenative silylation, but in 2017 the group of Luo reported the
131
first iron-catalyzed synthesis of 1-amino-2-silylalkanes through the 1,2-difunctionalization of
132
styrenes and conjugated alkenes (Scheme 5) [23]. Di-tert-butyl-peroxide (DTBP) was used as an
133
oxidant in the reaction. Amines, amides and carbon nucleophiles could be employed and delivered
134
the corresponding products in mostly good yields. The reaction was proposed to proceed via a
135
silicon-centered radical from oxidative cleavage of the Si-H bond followed by addition across the
136
C=C bond and a N-H oxidative functionalization cascade.
137
138
Scheme 4.Bao’s carboamination.
Organosilicon compounds have significant chemical, physical and bioactive properties and an example of these compounds is 1-amino-2-silylalkanes, which have, in recent times, emerged as candidates for pharmaceutical development. Silicon-containing compounds are generally made through hydrosylilation or dehydrogenative silylation, but in 2017 the group of Luo reported the first iron-catalyzed synthesis of 1-amino-2-silylalkanes through the 1,2-difunctionalization of styrenes and conjugated alkenes (Scheme5) [23]. Di-tert-butyl-peroxide (DTBP) was used as an oxidant in the reaction. Amines, amides and carbon nucleophiles could be employed and delivered the corresponding products in mostly good yields. The reaction was proposed to proceed via a silicon-centered radical from oxidative cleavage of the Si-H bond followed by addition across the C=C bond and a N-H oxidative functionalization cascade.
Molecules 2020, 25, x FOR PEER REVIEW 4 of 20
112
Scheme 3. Wang’s iron-catalyzed anti-Markovnikov hydroamination.
113
C-C and C-N bonds are important bonds in organic chemistry and one of the most effective
114
ways of creating these bonds simultaneously is through the carboamination of olefins. In 2017, the
115
group of Bao reported the diastereoselective construction of amines and disubstituted β-amino acids
116
through the carboamination of olefins (Scheme 4) [22]. Aliphatic acids were used as an alkyl source
117
and nitriles as a nitrogen source. The protocol could be performed on a gram-scale and various
118
carboamination products were obtained in good yields and excellent diastereoselectivity. The choice
119
of acid was found to have a strong effect on the diastereoselectivity. TsOH was used for the
120
carboamination of olefins, but for the carboamination of esters, binary and ternary acids had a more
121
positive effect over monoacids, with H2SO4 giving the best result. The addition of the nitrile group
122
was found, through Density Functional Theory (DFT) calculations, to be
123
diastereoselectivity-determining, and hyperconjugation was proposed to account for the
124
anti-selectivity.
125
126
Scheme 4. Bao’s carboamination.
127
Organosilicon compounds have significant chemical, physical and bioactive properties and an
128
example of these compounds is 1-amino-2-silylalkanes, which have, in recent times, emerged as
129
candidates for pharmaceutical development. Silicon-containing compounds are generally made
130
through hydrosylilation or dehydrogenative silylation, but in 2017 the group of Luo reported the
131
first iron-catalyzed synthesis of 1-amino-2-silylalkanes through the 1,2-difunctionalization of
132
styrenes and conjugated alkenes (Scheme 5) [23]. Di-tert-butyl-peroxide (DTBP) was used as an
133
oxidant in the reaction. Amines, amides and carbon nucleophiles could be employed and delivered
134
the corresponding products in mostly good yields. The reaction was proposed to proceed via a
135
silicon-centered radical from oxidative cleavage of the Si-H bond followed by addition across the
136
C=C bond and a N-H oxidative functionalization cascade.
137
138
Scheme 5.Luo’s silylation.
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2.2. C-H Bond Activation
The first example of a C-H activation was a Friedel–Crafts reaction reported by Dimroth in 1902, where benzene reacted with mercury (II) acetate to give phenylmercury (II) acetate [24].
Later, in 1955, Murahashi reported the cobalt-catalyzed chelation-assisted C-H functionalization of (E)-N-1-diphenylmethaneimine to 2-phenylisoindolin-1-one [25]. A great advance in the field occurred in 1966 when Shilov reported that K2PtCl4could induce isotope scrambling between methane and heavy water [26,27]. Shilov’s discovery led to the so called “Shilov system”, which remains to this day as one of the few catalytic systems that can accomplish selective alkene functionalizations under mild conditions. In 2008, the synthetic power of C-H activation was expanded to include organoiron catalysis by Nakamura in his arylation of benzoquinolines (Scheme6) [28]. An excellent review on the subject of iron in C-H activation reactions by Nakamura was published in 2017 [29] and a review on oxidative C-H activation was published by Li in 2014 [30].
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Scheme 5. Luo’s silylation.
139
2.2. C-H Bond Activation
140
The first example of a C-H activation was a Friedel–Crafts reaction reported by Dimroth in
141
1902, where benzene reacted with mercury (II) acetate to give phenylmercury (II) acetate [24]. Later,
142
in 1955, Murahashi reported the cobalt-catalyzed chelation-assisted C-H functionalization of
143
(E)-N-1-diphenylmethaneimine to 2-phenylisoindolin-1-one [25]. A great advance in the field
144
occurred in 1966 when Shilov reported that K2PtCl4 could induce isotope scrambling between
145
methane and heavy water [26,27]. Shilov’s discovery led to the so called “Shilov system”, which
146
remains to this day as one of the few catalytic systems that can accomplish selective alkene
147
functionalizations under mild conditions. In 2008, the synthetic power of C-H activation was
148
expanded to include organoiron catalysis by Nakamura in his arylation of benzoquinolines (Scheme
149
6) [28]. An excellent review on the subject of iron in C-H activation reactions by Nakamura was
150
published in 2017 [29] and a review on oxidative C-H activation was published by Li in 2014 [30].
151
152
Scheme 6. Nakamura’s C-H activation.
153
The group of Arnold has in the past used engineered cytochrome P450, which is a type of enzyme
154
that uses a heme cofactor, to enantioselectively α-hydroxylate arylacetic acid derivatives via C-H
155
activation [31]. In 2017, they reported the directed evolution of cytochrome P450 monooxygenase, for
156
enantioselective C-H activation to give C-N bonds (Scheme 7) [32]. It uses a variant of P411 based on
157
the P450 monooxygenase which has an axial serine ligand on the haem iron instead of the natural
158
cysteine. The method utilizes a tosyl azide as a nitrene source which generates an iron nitrenoid that
159
subsequently reacts with an alkane to deliver the C-H amination product. The P411 variant has a
160
turnover number (TON) of 1300, which is considerably higher than the best reported, to our
161
knowledge, for traditional chiral transition metal complexes, which is a chiral manganese porphyrin
162
with a turnover number of 85 [33]. A variety of benzylic tosylamines could be produced with excellent
163
ees.
164
165
Scheme 7. Arnold’s C-H amination.
166
In 2019, Arnold and coworkers extended their methodology using another variant of P411 in
167
C-H alkylation using diazoesters (Scheme 8) [34]. The diazo substrate scope could be extended
168
beyond ester-based reagents to Weinreb amides and diazoketones and gave the corresponding
169
products with excellent ees and with total turnover numbers (TTN) of up to 2330. These studies
170
together show the potential for generating C-H alkylation enzymes that can emulate the scope and
171
selectivity of Natures C-H oxygenation catalysts.
172
Scheme 6.Nakamura’s C-H activation.
The group of Arnold has in the past used engineered cytochrome P450, which is a type of enzyme that uses a heme cofactor, to enantioselectively α-hydroxylate arylacetic acid derivatives via C-H activation [31]. In 2017, they reported the directed evolution of cytochrome P450 monooxygenase, for enantioselective C-H activation to give C-N bonds (Scheme7) [32]. It uses a variant of P411 based on the P450 monooxygenase which has an axial serine ligand on the haem iron instead of the natural cysteine. The method utilizes a tosyl azide as a nitrene source which generates an iron nitrenoid that subsequently reacts with an alkane to deliver the C-H amination product. The P411 variant has a turnover number (TON) of 1300, which is considerably higher than the best reported, to our knowledge, for traditional chiral transition metal complexes, which is a chiral manganese porphyrin with a turnover number of 85 [33]. A variety of benzylic tosylamines could be produced with excellent ees.
Scheme 5. Luo’s silylation.
139
2.2. C-H Bond Activation
140
The first example of a C-H activation was a Friedel–Crafts reaction reported by Dimroth in
141
1902, where benzene reacted with mercury (II) acetate to give phenylmercury (II) acetate [24]. Later,
142
in 1955, Murahashi reported the cobalt-catalyzed chelation-assisted C-H functionalization of
143
(E)-N-1-diphenylmethaneimine to 2-phenylisoindolin-1-one [25]. A great advance in the field
144
occurred in 1966 when Shilov reported that K2PtCl4 could induce isotope scrambling between
145
methane and heavy water [26,27]. Shilov’s discovery led to the so called “Shilov system”, which
146
remains to this day as one of the few catalytic systems that can accomplish selective alkene
147
functionalizations under mild conditions. In 2008, the synthetic power of C-H activation was
148
expanded to include organoiron catalysis by Nakamura in his arylation of benzoquinolines (Scheme
149
6) [28]. An excellent review on the subject of iron in C-H activation reactions by Nakamura was
150
published in 2017 [29] and a review on oxidative C-H activation was published by Li in 2014 [30].
151
152
Scheme 6. Nakamura’s C-H activation.
153
The group of Arnold has in the past used engineered cytochrome P450, which is a type of enzyme
154
that uses a heme cofactor, to enantioselectively α-hydroxylate arylacetic acid derivatives via C-H
155
activation [31]. In 2017, they reported the directed evolution of cytochrome P450 monooxygenase, for
156
enantioselective C-H activation to give C-N bonds (Scheme 7) [32]. It uses a variant of P411 based on
157
the P450 monooxygenase which has an axial serine ligand on the haem iron instead of the natural
158
cysteine. The method utilizes a tosyl azide as a nitrene source which generates an iron nitrenoid that
159
subsequently reacts with an alkane to deliver the C-H amination product. The P411 variant has a
160
turnover number (TON) of 1300, which is considerably higher than the best reported, to our
161
knowledge, for traditional chiral transition metal complexes, which is a chiral manganese porphyrin
162
with a turnover number of 85 [33]. A variety of benzylic tosylamines could be produced with excellent
163
ees.
164
165
Scheme 7. Arnold’s C-H amination.
166
In 2019, Arnold and coworkers extended their methodology using another variant of P411 in
167
C-H alkylation using diazoesters (Scheme 8) [34]. The diazo substrate scope could be extended
168
beyond ester-based reagents to Weinreb amides and diazoketones and gave the corresponding
169
products with excellent ees and with total turnover numbers (TTN) of up to 2330. These studies
170
together show the potential for generating C-H alkylation enzymes that can emulate the scope and
171
selectivity of Natures C-H oxygenation catalysts.
172
Scheme 7.Arnold’s C-H amination.
In 2019, Arnold and coworkers extended their methodology using another variant of P411 in C-H alkylation using diazoesters (Scheme8) [34]. The diazo substrate scope could be extended beyond ester-based reagents to Weinreb amides and diazoketones and gave the corresponding products with excellent ees and with total turnover numbers (TTN) of up to 2330. These studies together show the potential for generating C-H alkylation enzymes that can emulate the scope and selectivity of Natures C-H oxygenation catalysts.
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173
Scheme 8. Arnold’s sp3 C-H activation.
174
C(sp3)-H alkylation via an isoelectronic iron carbene intermediate was first reported in 2017 by
175
the group of White using an iron phthalocyanine (Scheme 9) [35]. Iron carbenes generally prefer
176
cyclopropanation over C-H oxidation, but, in this case, allylic and benzylic C(sp3)-H bonds could be
177
alkylated with a broad scope. Mechanistic studies indicated that an electrophilic iron carbene was
178
mediating homolytic C-H cleavage followed by recombination with the resulting alkyl radical to
179
form the new C-C bond. The C-H cleavage was found to be partially rate determining.
180
181
Scheme 9. White’s isoelectronic carbene C(sp3)-H oxidation.
182
In 2018, the group of Ackermann reported on an allene annulation through an iron-catalyzed
183
C-H/N-H/C-O/C-H functionalization sequence (Scheme 10) [36]. The mechanism was shown to
184
involve an unprecedented 1,4-iron migration C-H activation manifold. Alkyl chlorides were
185
tolerated under these reaction conditions, with no cross-coupling being observed. Various
186
dihydroisoquinolones could be produced through the use of this method in excellent yields and the
187
modular nature of the triazole group allowed for the synthesis of exo-methylene isoquinolones as
188
well.
189
190
Scheme 10. Ackermann’s allene annulation.
191
In late 2019, the group of Wang demonstrated an iron-catalyzed α-C-H functionalization of
192
π-bonds in the hydroxyalkylation of alkynes and olefins (Scheme 11) [37]. Propargylic and allylic
193
C-H bonds were functionalized with this method and a wide variety of homopropargylic and
194
homoallylic alcohols could be produced in excellent yields, although with modest stereoselectivity.
195
The key to the success of this approach is the fact that coordination of the iron catalyst to the
196
unsaturated bond is known to lower the pKa of a propargylic or allylic proton from ≈38 and ≈43,
197
respectively, to <10 [38]. An (α-allenyl)iron or (π-allyl)iron complex for propargylic or allylic
198
complexes, respectively, is then formed in the presence of a base, which is utilized as the coupling
199
partner.
200
Scheme 8.Arnold’s sp3C-H activation.
C(sp3)-H alkylation via an isoelectronic iron carbene intermediate was first reported in 2017 by the group of White using an iron phthalocyanine (Scheme9) [35]. Iron carbenes generally prefer cyclopropanation over C-H oxidation, but, in this case, allylic and benzylic C(sp3)-H bonds could be alkylated with a broad scope. Mechanistic studies indicated that an electrophilic iron carbene was mediating homolytic C-H cleavage followed by recombination with the resulting alkyl radical to form the new C-C bond. The C-H cleavage was found to be partially rate determining.
Molecules 2020, 25, x FOR PEER REVIEW 6 of 20
173
Scheme 8. Arnold’s sp3 C-H activation.
174
C(sp3)-H alkylation via an isoelectronic iron carbene intermediate was first reported in 2017 by
175
the group of White using an iron phthalocyanine (Scheme 9) [35]. Iron carbenes generally prefer
176
cyclopropanation over C-H oxidation, but, in this case, allylic and benzylic C(sp3)-H bonds could be
177
alkylated with a broad scope. Mechanistic studies indicated that an electrophilic iron carbene was
178
mediating homolytic C-H cleavage followed by recombination with the resulting alkyl radical to
179
form the new C-C bond. The C-H cleavage was found to be partially rate determining.
180
181
Scheme 9. White’s isoelectronic carbene C(sp3)-H oxidation.
182
In 2018, the group of Ackermann reported on an allene annulation through an iron-catalyzed
183
C-H/N-H/C-O/C-H functionalization sequence (Scheme 10) [36]. The mechanism was shown to
184
involve an unprecedented 1,4-iron migration C-H activation manifold. Alkyl chlorides were
185
tolerated under these reaction conditions, with no cross-coupling being observed. Various
186
dihydroisoquinolones could be produced through the use of this method in excellent yields and the
187
modular nature of the triazole group allowed for the synthesis of exo-methylene isoquinolones as
188
well.
189
190
Scheme 10. Ackermann’s allene annulation.
191
In late 2019, the group of Wang demonstrated an iron-catalyzed α-C-H functionalization of
192
π-bonds in the hydroxyalkylation of alkynes and olefins (Scheme 11) [37]. Propargylic and allylic
193
C-H bonds were functionalized with this method and a wide variety of homopropargylic and
194
homoallylic alcohols could be produced in excellent yields, although with modest stereoselectivity.
195
The key to the success of this approach is the fact that coordination of the iron catalyst to the
196
unsaturated bond is known to lower the pKa of a propargylic or allylic proton from ≈38 and ≈43,
197
respectively, to <10 [38]. An (α-allenyl)iron or (π-allyl)iron complex for propargylic or allylic
198
complexes, respectively, is then formed in the presence of a base, which is utilized as the coupling
199
partner.
200
Scheme 9.White’s isoelectronic carbene C(sp3)-H oxidation.
In 2018, the group of Ackermann reported on an allene annulation through an iron-catalyzed C-H/N-H/C-O/C-H functionalization sequence (Scheme10) [36]. The mechanism was shown to involve an unprecedented 1,4-iron migration C-H activation manifold. Alkyl chlorides were tolerated under these reaction conditions, with no cross-coupling being observed. Various dihydroisoquinolones could be produced through the use of this method in excellent yields and the modular nature of the triazole group allowed for the synthesis of exo-methylene isoquinolones as well.
Molecules 2020, 25, x FOR PEER REVIEW 6 of 20
173
Scheme 8. Arnold’s sp3 C-H activation.
174
C(sp3)-H alkylation via an isoelectronic iron carbene intermediate was first reported in 2017 by
175
the group of White using an iron phthalocyanine (Scheme 9) [35]. Iron carbenes generally prefer
176
cyclopropanation over C-H oxidation, but, in this case, allylic and benzylic C(sp3)-H bonds could be
177
alkylated with a broad scope. Mechanistic studies indicated that an electrophilic iron carbene was
178
mediating homolytic C-H cleavage followed by recombination with the resulting alkyl radical to
179
form the new C-C bond. The C-H cleavage was found to be partially rate determining.
180
181
Scheme 9. White’s isoelectronic carbene C(sp3)-H oxidation.
182
In 2018, the group of Ackermann reported on an allene annulation through an iron-catalyzed
183
C-H/N-H/C-O/C-H functionalization sequence (Scheme 10) [36]. The mechanism was shown to
184
involve an unprecedented 1,4-iron migration C-H activation manifold. Alkyl chlorides were
185
tolerated under these reaction conditions, with no cross-coupling being observed. Various
186
dihydroisoquinolones could be produced through the use of this method in excellent yields and the
187
modular nature of the triazole group allowed for the synthesis of exo-methylene isoquinolones as
188
well.
189
190
Scheme 10. Ackermann’s allene annulation.
191
In late 2019, the group of Wang demonstrated an iron-catalyzed α-C-H functionalization of
192
π-bonds in the hydroxyalkylation of alkynes and olefins (Scheme 11) [37]. Propargylic and allylic
193
C-H bonds were functionalized with this method and a wide variety of homopropargylic and
194
homoallylic alcohols could be produced in excellent yields, although with modest stereoselectivity.
195
The key to the success of this approach is the fact that coordination of the iron catalyst to the
196
unsaturated bond is known to lower the pKa of a propargylic or allylic proton from ≈38 and ≈43,
197
respectively, to <10 [38]. An (α-allenyl)iron or (π-allyl)iron complex for propargylic or allylic
198
complexes, respectively, is then formed in the presence of a base, which is utilized as the coupling
199
partner.
200
Scheme 10.Ackermann’s allene annulation.
In late 2019, the group of Wang demonstrated an iron-catalyzed α-C-H functionalization of π-bonds in the hydroxyalkylation of alkynes and olefins (Scheme11) [37]. Propargylic and allylic C-H bonds were functionalized with this method and a wide variety of homopropargylic and homoallylic alcohols could be produced in excellent yields, although with modest stereoselectivity. The key to the success of this approach is the fact that coordination of the iron catalyst to the unsaturated bond is known to lower the pKa of a propargylic or allylic proton from ≈38 and ≈43, respectively, to<10 [38].
An (α-allenyl)iron or (π-allyl)iron complex for propargylic or allylic complexes, respectively, is then formed in the presence of a base, which is utilized as the coupling partner.
Molecules 2020, 25, x FOR PEER REVIEW 7 of 20
201
Scheme 11. Wang’s α-C-H functionalization.
202
In 2018, the group of Liu reported the unprecedented iron(II)-catalyzed fluorination of C(sp3)-H
203
bonds using alkoxyl radicals (Scheme 12) [39]. The procedure was applied to a wide range of
204
substrates and it was found that a range of functional groups were tolerated, including halide and
205
hydroxyl groups. N-fluorobenzenesulfonamide (NFSI) was used as the fluoride source and the
206
substrate scope could be extended from fluorination to chlorination, amination and alkylation. The
207
authors also demonstrated a one-pot application of their protocol starting from a simple alkane.
208
209
Scheme 12. Liu’s C-H fluorination.
210
2.3. Cross-Coupling Reactions
211
Transition-metal-catalyzed cross coupling protocols have become an important tool in the
212
organic chemist‘s arsenal. This area has been important in chemistry for about five decades, and in
213
2010 it received formal recognition when Richard Heck, Akira Suzuki and Ei-ichi Negishi received
214
the Nobel prize for palladium-catalyzed cross-couplings in organic synthesis. Although a powerful
215
technique, its applications have been dominated by the use of expensive palladium- and
216
nickel-based catalysts, which are often toxic. The most common types of cross coupling reactions
217
using iron are those involving Grignard reagents as the transmetalating nucleophile. The first
218
example of an alkenylation of alkyl Grignard reagents with organic halides using iron(III) chloride
219
was reported in 1971 by Kochi and Tamura (Scheme 13) [40]. A review on the subject of
220
iron-catalyzed cross-coupling reactions with a focus on mechanistic studies was published in 2016
221
by Byers [41]. A more focused review on the use of iron-catalyzed cross-coupling for the synthesis of
222
pharmaceuticals was released in 2018 by Szostak [42].
223
224
Scheme 13. Kochi’s and Tamura’s original alkenylation.
225
In 2016, Bäckvall and coworkers reported the coupling of propargyl carboxylates and Grignard
226
reagents using the environmentally benign Fe(acac)3 to synthesize substituted allenes and protected
227
α-allenols (Scheme 14) [43,44]. The mild reaction conditions tolerate a broad range of functional
228
groups (silyl ethers, carbamates and acetals) and could be applied to more complex molecules such
229
as steroids. Tri and tetra substituted allenes were obtained in excellent yields, whereas the yield was
230
found to drop for less substituted allenes. A variety of alkyl and aryl Grignard reagents could be
231
applied and it was demonstrated that the protocol can be readily performed on a gram-scale.
232
Scheme 11.Wang’s α-C-H functionalization.
In 2018, the group of Liu reported the unprecedented iron(II)-catalyzed fluorination of C(sp3)-H bonds using alkoxyl radicals (Scheme12) [39]. The procedure was applied to a wide range of substrates and it was found that a range of functional groups were tolerated, including halide and hydroxyl groups. N-fluorobenzenesulfonamide (NFSI) was used as the fluoride source and the substrate scope could be extended from fluorination to chlorination, amination and alkylation. The authors also demonstrated a one-pot application of their protocol starting from a simple alkane.
Molecules 2020, 25, x FOR PEER REVIEW 7 of 20
201
Scheme 11. Wang’s α-C-H functionalization.
202
In 2018, the group of Liu reported the unprecedented iron(II)-catalyzed fluorination of C(sp3)-H
203
bonds using alkoxyl radicals (Scheme 12) [39]. The procedure was applied to a wide range of
204
substrates and it was found that a range of functional groups were tolerated, including halide and
205
hydroxyl groups. N-fluorobenzenesulfonamide (NFSI) was used as the fluoride source and the
206
substrate scope could be extended from fluorination to chlorination, amination and alkylation. The
207
authors also demonstrated a one-pot application of their protocol starting from a simple alkane.
208
209
Scheme 12. Liu’s C-H fluorination.
210
2.3. Cross-Coupling Reactions
211
Transition-metal-catalyzed cross coupling protocols have become an important tool in the
212
organic chemist‘s arsenal. This area has been important in chemistry for about five decades, and in
213
2010 it received formal recognition when Richard Heck, Akira Suzuki and Ei-ichi Negishi received
214
the Nobel prize for palladium-catalyzed cross-couplings in organic synthesis. Although a powerful
215
technique, its applications have been dominated by the use of expensive palladium- and
216
nickel-based catalysts, which are often toxic. The most common types of cross coupling reactions
217
using iron are those involving Grignard reagents as the transmetalating nucleophile. The first
218
example of an alkenylation of alkyl Grignard reagents with organic halides using iron(III) chloride
219
was reported in 1971 by Kochi and Tamura (Scheme 13) [40]. A review on the subject of
220
iron-catalyzed cross-coupling reactions with a focus on mechanistic studies was published in 2016
221
by Byers [41]. A more focused review on the use of iron-catalyzed cross-coupling for the synthesis of
222
pharmaceuticals was released in 2018 by Szostak [42].
223
224
Scheme 13. Kochi’s and Tamura’s original alkenylation.
225
In 2016, Bäckvall and coworkers reported the coupling of propargyl carboxylates and Grignard
226
reagents using the environmentally benign Fe(acac)3 to synthesize substituted allenes and protected
227
α-allenols (Scheme 14) [43,44]. The mild reaction conditions tolerate a broad range of functional
228
groups (silyl ethers, carbamates and acetals) and could be applied to more complex molecules such
229
as steroids. Tri and tetra substituted allenes were obtained in excellent yields, whereas the yield was
230
found to drop for less substituted allenes. A variety of alkyl and aryl Grignard reagents could be
231
applied and it was demonstrated that the protocol can be readily performed on a gram-scale.
232
Scheme 12.Liu’s C-H fluorination.
2.3. Cross-Coupling Reactions
Transition-metal-catalyzed cross coupling protocols have become an important tool in the organic chemist‘s arsenal. This area has been important in chemistry for about five decades, and in 2010 it received formal recognition when Richard Heck, Akira Suzuki and Ei-ichi Negishi received the Nobel prize for palladium-catalyzed cross-couplings in organic synthesis. Although a powerful technique, its applications have been dominated by the use of expensive palladium- and nickel-based catalysts, which are often toxic. The most common types of cross coupling reactions using iron are those involving Grignard reagents as the transmetalating nucleophile. The first example of an alkenylation of alkyl Grignard reagents with organic halides using iron(III) chloride was reported in 1971 by Kochi and Tamura (Scheme13) [40]. A review on the subject of iron-catalyzed cross-coupling reactions with a focus on mechanistic studies was published in 2016 by Byers [41]. A more focused review on the use of iron-catalyzed cross-coupling for the synthesis of pharmaceuticals was released in 2018 by Szostak [42].
Molecules 2020, 25, x FOR PEER REVIEW 7 of 20
201
Scheme 11. Wang’s α-C-H functionalization.
202
In 2018, the group of Liu reported the unprecedented iron(II)-catalyzed fluorination of C(sp3)-H
203
bonds using alkoxyl radicals (Scheme 12) [39]. The procedure was applied to a wide range of
204
substrates and it was found that a range of functional groups were tolerated, including halide and
205
hydroxyl groups. N-fluorobenzenesulfonamide (NFSI) was used as the fluoride source and the
206
substrate scope could be extended from fluorination to chlorination, amination and alkylation. The
207
authors also demonstrated a one-pot application of their protocol starting from a simple alkane.
208
209
Scheme 12. Liu’s C-H fluorination.
210
2.3. Cross-Coupling Reactions
211
Transition-metal-catalyzed cross coupling protocols have become an important tool in the
212
organic chemist‘s arsenal. This area has been important in chemistry for about five decades, and in
213
2010 it received formal recognition when Richard Heck, Akira Suzuki and Ei-ichi Negishi received
214
the Nobel prize for palladium-catalyzed cross-couplings in organic synthesis. Although a powerful
215
technique, its applications have been dominated by the use of expensive palladium- and
216
nickel-based catalysts, which are often toxic. The most common types of cross coupling reactions
217
using iron are those involving Grignard reagents as the transmetalating nucleophile. The first
218
example of an alkenylation of alkyl Grignard reagents with organic halides using iron(III) chloride
219
was reported in 1971 by Kochi and Tamura (Scheme 13) [40]. A review on the subject of
220
iron-catalyzed cross-coupling reactions with a focus on mechanistic studies was published in 2016
221
by Byers [41]. A more focused review on the use of iron-catalyzed cross-coupling for the synthesis of
222
pharmaceuticals was released in 2018 by Szostak [42].
223
224
Scheme 13. Kochi’s and Tamura’s original alkenylation.
225
In 2016, Bäckvall and coworkers reported the coupling of propargyl carboxylates and Grignard
226
reagents using the environmentally benign Fe(acac)3 to synthesize substituted allenes and protected
227
α-allenols (Scheme 14) [43,44]. The mild reaction conditions tolerate a broad range of functional
228
groups (silyl ethers, carbamates and acetals) and could be applied to more complex molecules such
229
as steroids. Tri and tetra substituted allenes were obtained in excellent yields, whereas the yield was
230
found to drop for less substituted allenes. A variety of alkyl and aryl Grignard reagents could be
231
applied and it was demonstrated that the protocol can be readily performed on a gram-scale.
232
Scheme 13.Kochi’s and Tamura’s original alkenylation.
In 2016, Bäckvall and coworkers reported the coupling of propargyl carboxylates and Grignard reagents using the environmentally benign Fe(acac)3to synthesize substituted allenes and protected α-allenols (Scheme14) [43,44]. The mild reaction conditions tolerate a broad range of functional groups (silyl ethers, carbamates and acetals) and could be applied to more complex molecules such as steroids.
Tri and tetra substituted allenes were obtained in excellent yields, whereas the yield was found to drop for less substituted allenes. A variety of alkyl and aryl Grignard reagents could be applied and it was demonstrated that the protocol can be readily performed on a gram-scale.
Molecules 2020, 25, 1349 8 of 20
Molecules 2020, 25, x FOR PEER REVIEW 8 of 20
233
Scheme 14. Bäckvall’s synthesis of substituted allenes and protected α-allenols from carboxylates.
234
In 2016, the group of Frantz reported on a highly stereoselective iron-catalyzed cross coupling
235
using FeCl3 to couple Grignard reagents and enol carbamates (Scheme 15) [45]. Many functional
236
groups, such as ethers, silanes, primary bromides, alkynes and alkenes, were tolerated. In almost all
237
cases, the yield and E/Z selectivity was excellent, with (E)-carbamates leading to (E)-acrylates and
238
(Z)-carbamates leading to (Z)-acrylates. This study constitutes the only example so far of an
239
iron-catalyzed cross-coupling, where an oxygen-based electrophile is favored over a vinylic halide (a
240
Cl group at R2 in Scheme 15).
241
242
Scheme 15. Frantz’ stereoselective synthesis of acrylates.
243
Aryl C-glycosides are interesting pharmaceutical candidates because of their biological
244
activities and resistance to metabolic degradation. In 2017, the group of Nakamura developed a
245
highly diastereoselective iron-catalyzed cross-coupling of glycosyl halides and aryl metal reagents to
246
form these compounds using FeCl2 in conjunction with a SciOPP ligand (Scheme 16) [46]. A variety
247
of aryl, heteroaryl and vinyl metal reagents based on magnesium, zinc, boron and aluminium could
248
be applied. The reaction was found to proceed through the generation and stereoselective trapping
249
of glycosyl radical intermediates and represents a rare example of a highly stereoselective
250
carbon-carbon bond formation based on iron catalysis.
251
252
Scheme 16. Nakamura’s diastereoselective synthesis of aryl C-glycosides using (Sciopp) FeCl2.
253
Scheme 14.Bäckvall’s synthesis of substituted allenes and protected α-allenols from carboxylates.
In 2016, the group of Frantz reported on a highly stereoselective iron-catalyzed cross coupling using FeCl3to couple Grignard reagents and enol carbamates (Scheme15) [45]. Many functional groups, such as ethers, silanes, primary bromides, alkynes and alkenes, were tolerated. In almost all cases, the yield and E/Z selectivity was excellent, with (E)-carbamates leading to (E)-acrylates and (Z)-carbamates leading to (Z)-acrylates. This study constitutes the only example so far of an iron-catalyzed cross-coupling, where an oxygen-based electrophile is favored over a vinylic halide (a Cl group at R2in Scheme15).
Molecules 2020, 25, x FOR PEER REVIEW 8 of 20
233
Scheme 14. Bäckvall’s synthesis of substituted allenes and protected α-allenols from carboxylates.
234
In 2016, the group of Frantz reported on a highly stereoselective iron-catalyzed cross coupling
235
using FeCl3 to couple Grignard reagents and enol carbamates (Scheme 15) [45]. Many functional
236
groups, such as ethers, silanes, primary bromides, alkynes and alkenes, were tolerated. In almost all
237
cases, the yield and E/Z selectivity was excellent, with (E)-carbamates leading to (E)-acrylates and
238
(Z)-carbamates leading to (Z)-acrylates. This study constitutes the only example so far of an
239
iron-catalyzed cross-coupling, where an oxygen-based electrophile is favored over a vinylic halide (a
240
Cl group at R2 in Scheme 15).
241
242
Scheme 15. Frantz’ stereoselective synthesis of acrylates.
243
Aryl C-glycosides are interesting pharmaceutical candidates because of their biological
244
activities and resistance to metabolic degradation. In 2017, the group of Nakamura developed a
245
highly diastereoselective iron-catalyzed cross-coupling of glycosyl halides and aryl metal reagents to
246
form these compounds using FeCl2 in conjunction with a SciOPP ligand (Scheme 16) [46]. A variety
247
of aryl, heteroaryl and vinyl metal reagents based on magnesium, zinc, boron and aluminium could
248
be applied. The reaction was found to proceed through the generation and stereoselective trapping
249
of glycosyl radical intermediates and represents a rare example of a highly stereoselective
250
carbon-carbon bond formation based on iron catalysis.
251
252
Scheme 16. Nakamura’s diastereoselective synthesis of aryl C-glycosides using (Sciopp) FeCl2.
253
Scheme 15.Frantz’ stereoselective synthesis of acrylates.
Aryl C-glycosides are interesting pharmaceutical candidates because of their biological activities and resistance to metabolic degradation. In 2017, the group of Nakamura developed a highly diastereoselective iron-catalyzed cross-coupling of glycosyl halides and aryl metal reagents to form these compounds using FeCl2in conjunction with a SciOPP ligand (Scheme16) [46]. A variety of aryl, heteroaryl and vinyl metal reagents based on magnesium, zinc, boron and aluminium could be applied.
The reaction was found to proceed through the generation and stereoselective trapping of glycosyl radical intermediates and represents a rare example of a highly stereoselective carbon-carbon bond formation based on iron catalysis.
Molecules 2020, 25, x FOR PEER REVIEW 8 of 20
233
Scheme 14. Bäckvall’s synthesis of substituted allenes and protected α-allenols from carboxylates.
234
In 2016, the group of Frantz reported on a highly stereoselective iron-catalyzed cross coupling
235
using FeCl3 to couple Grignard reagents and enol carbamates (Scheme 15) [45]. Many functional
236
groups, such as ethers, silanes, primary bromides, alkynes and alkenes, were tolerated. In almost all
237
cases, the yield and E/Z selectivity was excellent, with (E)-carbamates leading to (E)-acrylates and
238
(Z)-carbamates leading to (Z)-acrylates. This study constitutes the only example so far of an
239
iron-catalyzed cross-coupling, where an oxygen-based electrophile is favored over a vinylic halide (a
240
Cl group at R2 in Scheme 15).
241
242
Scheme 15. Frantz’ stereoselective synthesis of acrylates.
243
Aryl C-glycosides are interesting pharmaceutical candidates because of their biological
244
activities and resistance to metabolic degradation. In 2017, the group of Nakamura developed a
245
highly diastereoselective iron-catalyzed cross-coupling of glycosyl halides and aryl metal reagents to
246
form these compounds using FeCl2 in conjunction with a SciOPP ligand (Scheme 16) [46]. A variety
247
of aryl, heteroaryl and vinyl metal reagents based on magnesium, zinc, boron and aluminium could
248
be applied. The reaction was found to proceed through the generation and stereoselective trapping
249
of glycosyl radical intermediates and represents a rare example of a highly stereoselective
250
carbon-carbon bond formation based on iron catalysis.
251
252
Scheme 16. Nakamura’s diastereoselective synthesis of aryl C-glycosides using (Sciopp) FeCl2.
